Differential effects of modern immunosuppressive agents on the development of intimal hyperplasia

Abstract

Modern immunosuppressive agents such as tacrolimus and rapamycin are claimed to be associated with a reduction in vascular narrowing, a central feature of chronic rejection. This study assesses the effect of cyclosporine, tacrolimus and rapamycin on the development of intimal thickening, fibrosis-associated genes and deposition of extracellular matrix (ECM) proteins in a model of intimal hyperplasia. Male Sprague-Dawley rats received either no treatment or 5 mg/kg cyclosporine, 0.1 mg/kg tacrolimus or 0.05 mg/kg rapamycin. Animals underwent left common carotid balloon angioplasty, and intima medial ratios, pro-fibrotic gene expression and ECM accumulation were calculated at 14 and 28 days. Cyclosporine was associated with increased intimal thickening compared to controls ( P < 0.004). Tacrolimus had no effect on intimal thickening, whilst rapamycin significantly inhibited intimal thickening at both 14 and 28 days ( P < 0.004 and P < 0.026, respectively). All groups significantly inhibited matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, transforming growth factor (TGF)-beta and collagen III expression at 14 days ( P < 0.001), but increased ECM deposition. However, rapamycin marginally reduced ECM deposition compared to cyclosporine ( P < 0.06). Treatment with cyclosporine was associated with worsening of vascular narrowing, whilst rapamycin showed a beneficial reduction in intimal thickening. Treatment with all immunosuppressive agents resulted in increased ECM deposition. Rapamycin may halt the progression of vascular narrowing compared to both cyclosporine and tacrolimus.

Simultaneous pancreas and kidney transplantation: Incidence and risk factors for amputation after 10‐year follow‐up

“…We considered whether tacrolimus could account for the increased risk of amputation. However, tacrolimus preserves endothelial function to prevent the development of intimal hyperplasia . Another potential hypothesis is a steal phenomenon caused by anastomosing the donor kidney and pancreas to the recipient's left and right common iliac arteries, respectively, as described by Sollinger et al .…”

Distinct Deleterious Effects of Cyclosporine and Tacrolimus and Combined Tacrolimus–Sirolimus on Endothelial Cells: Protective Effect of Defibrotide

“…Our results are consistent with previous data demonstrating that SIR has few damaging effects on the endothelium. SIR decreases vascular endothelial growth factor synthesis [26] and seems to prevent or limit intimal thickening [27]. SIR is the immunosuppressant of choice for renal transplantation and is being used more frequently in the HSCT setting.…”

Gastrointestinal hemorrhage due to complicated gastroduodenal ulcer disease in liver transplant patients taking sirolimus

“…Additionally, sirolimus has been shown to inhibit smooth muscle cell proliferation and intimal thickening, presumably by interfering with critical signaling pathways involved in proliferation or perhaps synthesis of local growth factors (8). Moreover, current data indicate a role in the wound healing response (9–11).…”